Alzheimer's disease (AD) is a degenerative disease of the chronic central nervous system and is the most common type of senile dementia. The early clinical manifestations are mainly the patients' decreased memory and decline in self-care ability, which ultimately leads to cognitive dysfunction and loss, neurobehavioral abnormality and complete loss of self-care ability. The course of disease is generally 6 to 12 years, and the patient often dies from concurrent infections. In 2010, Alzheimer's Disease International (ADI) reported and estimated that there are approximately 35.6 million people suffering from dementia worldwide, accounting for around 0.5% of the world's total population, the prevalence of dementia in people aged 60 years and over is 5%-7%, and is expected to reach 115.4 million in 2050. The total estimated expenses for treatment of dementia worldwide reached up to $604 billion in 2010, which is estimated to increase by 85% by 2030. According to the World Health Organization, by 2020, AD will become the fourth disease in China's disease burden. AD not only seriously affects patient's physical health and quality of life, but also imposes a heavy burden on the patient's family and on society. The elucidation of etiology and pathogenesis of AD, and the study of preventive and therapeutic methods have become an urgent medical and social problem to be solved.
Neuropathological features of AD include diffuse brain atrophy, deposition of extracellular neuritic plaques or senile plaques (SP), intracellular neurofibrillary tangle (NFT), and neuronal loss, accompanying with granulovacuolar degeneration and meningeal vascular amyloid degeneration, etc.
The etiology and pathogenesis of AD is very complicated, although the study of the etiology and pathogenesis of AD have been reported a lot, the pathogenesis of AD has not been fully elucidated so far, which is related to the complexity of the pathogenesis and the interaction of multiple factors. There are many hypotheses about the pathogenesis of AD, including cholinergic theory, β-Amyloid peptides (Aβ) deposition hypothesis, oxidative stress hypothesis, inflammation and immunology theory, microtubule-associated protein dysfunction hypothesis, insulin hypothesis, metal ion metabolism disorder hypothesis, gene mutation hypothesis, among others.
The amyloid cascade hypothesis has always occupied the main position of the pathogenesis of AD. The hypothesis posits that the abnormal metabolism of amyloid protein precursor (APP) in the brain increases the production of amyloid β-protein and decreases the degradation of amyloid β-protein, causing a large number of Aβ accumulation, and the excess Aβ accumulation forms amyloid plaques (i.e., senile plaques, SP), resulting in neurotoxicity. Therefore, AD therapeutic drugs targeting Aβ have become one of the main directions of clinical research.
Aβ Production and Metabolism
APP is an Aβ precursor protein. Under normal circumstances, APP has two hydrolysis pathways in human body. One is the non-Aβ generation pathway. APP is mainly hydrolyzed by α-secretase into a soluble APP alpha (soluble APP, sAPPα) containing partial Aβ sequence and a C83 carboxy-terminal fragment, and the latter is further degraded by γ-secretase. At present, sAPPα is known to have neurotrophic effects, and is capable of promoting the development of nerve cells and plays a role in neuronal cell protection by reducing intracellular Ca2+ concentration, which is related to learning and memory functions. However, an sAPPα deficiency has not been proven to be directly related to the pathogenesis of AD. This pathway is the main pathway for APP metabolism. The other is the Aβ generation pathway. APP is first hydrolyzed by β-secretase into sAPPβ and a C99 carboxy-terminal fragment, and the latter is further degraded by γ-secretase to produce Aβ42 or Aβ40. However, Aβ42 is more prone to form β-sheet structure and is easier to aggregate into oligomers and fibers, which is more cytotoxic than Aβ40. Meanwhile, recent studies have confirmed that soluble oligomeric Aβ is more neurotoxic than mature insoluble fibrous Aβ. There are many toxic mechanisms of Aβ. For example, Aβ can induce the brain neurons to produce oxygen free radicals, thus destroying the structure of nerve cell membranes, causing the function to be abnormal. In addition, Aβ may alter the distribution of neurotransmitters and signaling molecules. Aβ can also increase intracellular free calcium ions, and through various pathways to trigger mitochondrial dysfunction, axoplasmic transport dysfunction, and cause neuronal loss, etc. However, some researchers believe that Aβ is not a predictor of human death but a protective response to neuronal damage. At physiological concentrations of nanomolar, Aβ can be used as a nutritional factor with nutritional and neuroprotective effects. Zou et al. demonstrated that, at nanomolar concentrations Aβ42 monomer can be used as a nutrient factor to inhibit metal-induced oxidative stress. Some researchers also believe that in AD patients, the increase of Aβ production may exceed a physiological concentration, making it possible to acquire neurotoxic effects. Although the effect of Aβ in AD is still vague, when the concentration of Aβ increases to a certain level, the toxic effect is greater than the protective effect.
There are two main pathways for the Aβ metabolism: the enzymatic degradation pathway and the receptor-mediated transport out of the brain pathway.
To this end, the development of drugs targeting key links such as the production, aggregation and clearance of Aβ has become a research hotspot. The drugs targeting Aβ are mainly divided into the following categories:
Reduction of the Generation of Aβ
α-Secretase Agonists
At present, there are few reports on α-secretase research. α-secretase is a member of the family of a disintegrin and metalloproteinase (ADAM), up-regulating the activity thereof not only reduces the generation of Aβ, but also increases the generation of sAPPα with neuroprotective effects, which has potential AD therapeutic effects. The activity of α-secretase is regulated by protein kinase C (PKC) protein phosphorylation signal transduction pathway. Directly stimulating the activity of α-secretase or indirectly stimulating the activity of PKC and PKC pathway-related proteins can achieve to up-regulate the activity of α-secretase. Studies have found that certain statins, vitamin A drugs and neuropeptides (such as pituitary adenylate cyclase-activating peptide) can increase α-secretase activity or PKC activity.
β-Secretase Inhibitors
It is currently believed that there are two different β-secretases, BACE1 (β-site APP-cleaving enzyme 1) and BACE2. BACE1 has all the activities of β-secretase and is a key enzyme for Aβ generation. BACE2 is a homologous enzyme of BACE1, mainly distributed in the heart, kidney and placenta, but rarely distributed in brain tissue, which can compete with BACE1 for APP site, but cannot catalyze and form intact Aβ. Thus, it can be inferred that BACE2 does not play an important role in the generation of Aβ. Therefore, selective BACE1 inhibitors have potential AD therapeutic effects, but there are two major constraints: first of all, BACE1 has a very important physiological effect, and inhibiting the activity thereof may produce obvious toxic side effects. In addition, BACE1 has a larger active area, and the compounds required to inhibit the BACE1 activity is large in volume, while the large-volume compounds are difficult to pass through the blood-brain barrier. Because of these constraints, only a few compounds among the many BACE1 inhibitors have entered clinical trials.
γ-Secretase Inhibitors
γ-secretase acts as a key enzyme that directly catalyzes the generation of Aβ, inhibition of the γ-secretase activity is a very attractive target for the treatment of AD. Studies have found that in addition to acting on APP-related substrates, γ-secretase can also affect various physiological functions such as embryonic development, hematopoiesis, cell adhesion, and cell-cell interaction through the Notch signal transduction pathway, and non-specific inhibition of the γ-secretase activity can produce many significant and serious side effects. The focus of current research is mainly on finding highly selective γ-secretase inhibitors or regulators. In addition, some non-steroidal anti-inflammatory drugs (such as ibuprofen, indomethacin and sulindac sulfide, flurbiprofen, etc.) have the function of γ-secretase regulators. Among them, the results of phase II clinical trials of flurbiprofen (also known as tarenflurbil or MPC-7869) were gratifying. However, in the phase III clinical trials, completely negative results were obtained. It is analyzed that the reasons may be related to the limited inhibition of tarenflurbil to γ-secretase activity and the poor permeability of blood-brain barrier.
Drugs for Inhibition of Aβ Aggregation
Aβ aggregation is a multi-step process involving multiple intermediates that includes oligomers and fibrils. Tramiprosate is a polysaccharide analogue that can combine with Aβ to block and inhibit the formation of plaques. The results of phase II clinical trials showed that long-term use of tramiprosate is safe and can reduce Aβ42 in the cerebrospinal fluid. However, tramiprosate did not show significant effects in the phase III clinical trial and the test has been discontinued.
In addition, studies have found that metal ions in the brain, such as zinc ions and copper ions, can promote the polymerization of soluble Aβ and stabilize the Aβ polymer. PBT1 (clioquinol) is a metal complexing agent that can affect the interaction of copper and zinc ions with Aβ. Phase II clinical trials have found that the PBT1 is well tolerated, can effectively reduce the Aβ concentrations in plasma and reduce cognitive deterioration of AD patients (especially patients with severe AD). However, due to the manufacturing process, some high toxicity impurities remain in PBT1, which limits further application of PBT1. PBT2 is an analogue of PBT1, which shows anti-Aβ oligomerization effect of PBT2 is the same as or superior than anti-Aβ oligomerization effect of PBT1 in animal experiments. PBT2 has also entered the phase II clinical trial and found that PBT2 is safe and well tolerated, can effectively reduce the concentration of Aβ1-42 in the cerebrospinal fluid and has a certain improvement effect on the two executive functions of AD patients.
Promotion of the Clearance of Aβ
Two pathways of increasing the enzymatic degradation of Aβ and up-regulating receptor-mediated Aβ transport out of the brain are included.
Application of Retinoic Compounds in the Treatment of AD
Receptor subtype-selective retinoic compounds have good targeting properties and can reduce the toxic side effects of retinoic compounds, and thus are one of the main research directions of retinoic compounds. The receptor subtype-selective drugs currently on the market include tamibarotene and bexarotene. It has been reported that bexarotene can rapidly clear the β-amyloid protein deposited in the brain of laboratory mice with Alzheimer's symptoms-like disease, and is considered to have great potential for the treatment of Alzheimer's disease (Science, 2012, 335(6075): 1503-1506.).